Adult stem cells play an important role in replenishing the pool of highly differentiated but short-lived cells in different tissues. A unique feature of adult stem cells is their ability to both self-renew to maintain their population and undergo differentiation to replenish the cells of the tissue. Recent findings suggest that some cancers arise due to misregulation of mechanisms that regulate stem cells. Understanding the regulatory pathways that specify stem cell fate may thus inform new approaches for the treatment of cancer. Also, knowledge of stem cell regulation can provide strategies to manipulate adult stem cells in vivo to promote regeneration of damaged tissues. Studies have demonstrated that a key regulator of the decision between self-renewal and differentiation is the signal emanating from the niche cells surrounding the stem cells. The Drosophila male germ line is an excellent model to study interactions between the niche and stem cells in vivo. The niche signal that specifies stem cell self-renewal in the male germ line is well characterized but the downstream stem cell intrinsic regulatory pathways are unknown. The goal of this proposal is to identify cell intrinsic mechanisms that regulate male germ line stem cell behavior in response to the niche signal. The specific aims of this proposal are: 1) To examine the function of one of the genes expressed in the early germ cells, the FoxN class transcription factor, jumu, in specifying stem cell fate by loss and gain of function analysis. 2) To identify genes whose expression is directly regulated by STAT, the transcription factor activated in the stem cells in response to the niche signal, using chromatin immunoprecipitation. The function of these genes in germ line stem cells will be determined by mutational analysis.3) To identify stem cell intrinsic regulatory networks;genes expressed in the stem cell enriched population will be compared to those expressed in committed progenitor cells by microarray analysis. This will help identify mRNAs expressed in stem cells that shut down or are degraded as stem cells differentiate as well as processes that turn on as cells initiate differentiation. Relevance: The goal of this proposal is to identify mechanisms that regulate stem cell behavior in the male germ line of Drosophila;this study may provide models for the regulation of mammalian adult stem cells. Understanding stem cell regulation will be helpful in harnessing the potential of adult stem cells to regenerate damaged tissues. Also, there is evidence that some cancers arise due to defects in stem cell regulation and understanding stem cell behavior can present new strategies to treat cancer.